Psychological stress has been shown to compromise several components of the natural immune system that can leave the host at risk for infection. Infections occur in 2-20% of surgery patients (Samson 2004) depending on the site. On average, infection increases the patient's hospitalization time by 10.2 days (Zoutman 1998) and the cost of treatment by $17,708 (Whitehouse 2002). Psychological stress has been shown to delay wound closure in humans and animals. Also, experimental wounds placed in stressed mice contain greater than 4 logs more bacteria than wounds of control mice (Rojas et al., 2002), demonstrating weakened microbial clearance. Two pathways are likely to be important, the hypothalamic pituitary adrenal axis (HPA) and the sympathetic nervous system (SNS). Activation of the HPA axis results in the release of glucocorticoids and epinephrine, which are known to inhibit the immune system. The SNS in this model appears to have its main effect on vasoconstriction of blood vessels leading to impaired oxygen delivery to the tissue. Oxygen is critical to microbial clearance and therefore is likely to play an important role in stress-impaired microbial clearance. The objective of this proposal is to determine the mechanisms by which stress impairs microbial clearance using a well-characterized, naturalistic wound model of infection and to begin to develop approaches to improve and restore these effects. We will also verify our finding in a clinically relevant incisional model. The specific aims of this study are to: 1) characterize the effects of stress on the role of the natural immune system during wound healing, 2) determine the relative/combined roles of the HPA axis and sympathetic nervous system in stress impaired microbial clearance, and 3) determine the role of oxygen on stress-impaired microbial clearance during healing. Stress is a component of our everyday lives and it has been proven that activities from academic examinations to care giving for Alzheimer's patients result in delayed wound closure by 40% and 24% respectively (Marucha et al. 1998; Kiecolt-Glaser, Marucha et al. 1995, see appendix). The goal of this project is to identify the mechanisms which underlie stress-impaired microbial clearance and ultimately develop appropriate therapy.